Prostaglandins have been known for some time to play a major role in the inflammation process, and have been shown to be involved in the pathophysiology of several chronic human diseases. They are involved as mediators of pain, edema and vascular permeability in arthritic diseases such as rheumatoid arthritis and osteoarthritis (Lewis and Kreft, Immunopharmacol. Immunotoxicol. 17, 607-663 (1995)). In addition, prostaglandins have been postulated to be involved in the pathophysiology of colorectal cancer (Marcus, New Eng. J. Med., 333, 656-657 (1995); Huang and Heimbrook, Exp.Opin. Invest. Drugs., 4 (3), 243-249 (1995)). Thus an agent that inhibits prostaglandin synthesis may be useful in treating these disorders.
The biosynthesis of prostaglandins was previously thought to be due to the action of a single cyclooxygenase enzyme on arachidonic acid to afford prostaglandin H.sub.2 (Vane et al, Postgrad. Med. J. , 66 (Suppl 4), S2-S17 (1990); Lewis and Kreft, Immunopharmacol. Immunotoxicol. 17, 607-663 (1995)). This intermediate is subsequently transformed into the various members of the prostaglandin family by more distal enzymes. The clinical utility of cyclooxygenase inhibitors (often called NSAIDs; nonsteroidal antiinflammatory drugs) is well established in arthritic disorders (Brooks et al, New Eng. J. Med., 324, 1716-1725 (1991)). However, these compounds also affect other prostaglandin-regulated processes not associated with inflammation but rather, with maintenance of gastrointestinal integrity and renal blood flow (Dajani et al. J. Physiol. Pharmacol., 46, 3-16 (1995); Somasundaram et al. Scand. J. Gastroenterol., 30, 289-299 (1995)), via a mechanism involving inhibition of prostaglandin G/H synthase or cycloxygenase (COX). Thus, at high doses often necessary to show therapeutic efficacy, most NSAIDs show severe gastric and renal side effects, including life threatening ulcers that limit their therapeutic utility. An alternative to NSAIDs is the use of corticosteroids, which have even more severe liabilities, especially when long term therapy is involved.
Under the old paradigm of a single cyclooxygenase enzyme, it appeared that the selective inhibition of prostaglandin synthesis in inflamed tissue versus inhibition of prostaglandin synthesis in G.I. tissue was unlikely unless tissue specificity could be achieved.
Recently, the discovery that there are two distinct cyclooxygenase isozymes in the arachidonic acid/prostaglandin pathway, has given rise to a new paradigm which may lead to compounds that have a separation of inhibition of prostaglandin synthesis in inflamed tissue from inhibition of prostaglandin synthesis in G.I. tissue (Haylar, Lancet, 346, 521-522 (1995), Lewis and Kreft, Immunopharmacol. Immunotoxicol. 17, 607-663 (1995)). In the new paradigm the constitutive cyclooxygenase enzyme responsible for prostaglandin synthesis in G.I. tissue is termed COX-1 and the inducible cyclooxygenase enzyme (reported by Hla and Nielson, Proc. Ntl. Acad. Sci. USA, 89, 7384 (1992)) responsible for prostaglandin synthesis in inflamed tissue is termed COX-2. COX-1 appears to have a physiological role being involved in maintenance of gastrointestinal integrity and renal blood flow, while COX-2 appears to be mainly responsible for the pathological effects of prostaglandins.
Several groups have reported that NSAIDS vary in their ability to inhibit COX-1 and COX-2 so that selective inhibition may be possible (O'Neill et al, Molec. Pharmacol., 45, 245-254 (1994); Laneuville et al, J. Pharmacol. Exp. Ther., 271, 927-934 (1994); Mitchell et al, Proc Natl. Acad Sci. USA, 90, 11693-11697 (1993)). The current opinion suggests that a selective inhibitor of COX-2 will have clinical efficacy in inflammatory diseases with reduced potential for gastrointestinal toxicity and renal side effects. There is evidence from animal models to support this hypothesis (Chan et. al J. Pharmacol. Exp. Ther. 274, 1531-1537 (1995); Masferrer et. al. Proc. Natl. Acad. Sci. USA, 91, 3228-3232 (1994); Seibert et al.. Proc. Natl. Acad. Sci. USA, 91, 12013-12017 (1994)). Moreover, this may be the mechanism behind the improved G.I. safety of the NSAID etodolac, which has been reported to show a tenfold selectivity for inhibition of COX-2 (Glaser et al. Eur. J. Pharmacol. 281, 107-111 (1995)).
Indomethacin, a relatively non-selective inhibitor of COX-1 and COX-2 has been shown to be useful in the treatment of Alzheimer's disease (Rogers et al., Neurology 43, 1609-1611 (1993)). These findings suggest that novel COX-2 inhibitors would be attractive targets for the treatment of Alzheimer disease and for antiarthritic therapy with reduced potential for gastrointestinal toxicity and renal side effects. In addition, the COX-2 enzyme has been shown to be upregulated in colorectal cancer and a selective COX-2 inhibitor may also be of use in this disease (Sano et. al. Cancer Res.., 55, 3785-3789 (1995); Huang and Heimbrook, Exp. Opin. Invest. Drugs 4 (3), 243-249, (1995)).
Certain tetronic, thiotetronic and tetramic acid derivatives are described in U.S. Pat. No. 5,420,153 as phospholipase A.sub.2 inhibitors with antiinflammatory properties, and modulators of PAF-mediated biological processes useful as antifertility agents.
Certain substituted indenyl acetic acids are described in U.S. Pat. Nos. 3,654,349 and 3,647,858 with antiinflammatory, antipyretic and analgesic properties.
The above-cited patents disclose compounds that are structurally different from the compounds of the present invention. In addition, the compounds of the present invention are cycloxygenase inhibitors, and unexpectedly exhibit marked selectivity for the inhibition of COX-2 over COX-1. The compounds disclosed in each of the patents cited above unlike the compounds of the present invention, do not act as preferential inhibitors of COX-2; thus, they are not expected to exhibit any of the advantages of the compounds of the present invention, i.e. they are not expected to produce a reduced amount of side effects.